Aryl substituted-hydroxy substituted cyclohexanecarboxylic acids

ABSTRACT

HYDROXYACIDS AND HYDROXYESTERS OF THE FORMULA:   1-(HO-),1-AR,2,3-DI(R&#39;&#39;),4-(ROOC-)-CYCLOHEXANE   WHEREIN R IS HYDROGEN OR LOWER ALKYL, R&#39;&#39; IS LOWER ALKYL AND AR IS SUBSTITUTED ARYL, ARE INTERMEDICATES IN THE PREPARATION OF 2-LOWER ALKYL-3-LOWER ALKYL-4-CYCLOHEXENECARBOXYLIC ACIDS AND ESTERS WHICH ARE ACTIVE AGENTS FOR THE SUPPRESSION OF ANIMAL REPRODUCTION.

United States Patent US. C]. 2260-3453 4 Claims ABSTRACT OF THE DISCLOSURE Hydroxyacids and hydroxyesters of the formula:

OH C 0 OR iv it wherein R is hydrogen or lower alkyl, R is lower alkyl and Ar is substituted aryl, are intermediates in the preparation of 2-lower alky1-3-lower alkyl-4-aryl-cyclohexenecarboxylic acids and esters which are active agents for the suppression of animal reproduction.

This is a division of application Ser. No. 662,295, filed Aug. 22, 1967 and now US. Pat. No. 3,567,770.

The compounds of the present invention are of the formula:

0H 0 o 0 R Au wherein R is hydrogen or lower alkyl of up to 8 carbon atoms, R is lower alkyl of up to 6 carbon atoms and Ar is wherein R is hydrogen, hydroxy, lower alkoxy of up to 4 carbon atoms, lower acyloxy of up to carbon atoms or tetrahydropyranyl-Z-oxy, R is hydrogen, hydroxy, lower alkyl of up to 4 carbon atoms, lower alkoxy of up to 4 carbon atoms, lower acyloxy of up to 5 carbon atoms, chlorine, tetrahydropyranyl-Z-oxy or trifluoromethyl and R is hydrogen, hydroxy, lower alkyl of up to 4 carbon atoms, lower acyloxy of up to 5 carbon atoms, diethylaminoethoxy, thiornethyl, trifl-uoromethyl, dimethylamino or tetrahydropyranyl-Z-oxy, and wherein at least 1 and not more than 2 of R R and R is hydrogen; 3,4-methylenedioxyphenyl, u-naphthyl or fl-naphthyl.

The compounds of the present invention are prepared by the saponification of their corresponding lactones or by the reaction of aryl Grignard reagent or an aryl lithium compound and a 2-lower alkyl-3-lower alkyl-4- ketocyclohexanecarboxylic acid. The preparation of the lactones is disclosed in my copending application Ser. No.

662,282 filed Aug. 22, 1967 and now abandoned. The utility of the 2-lower alkyl-3-lower alkyl-4-aryl-cyclohexenecarboxylic acids and esters prepared from the compounds of the present invention is fully described in my copending application Ser. No. 622,311, filed Aug. 22, 1967 and now abandoned.

The preparation of the compounds of the invention is illustrated by the following reaction schemes:

NaOH

0H o 0 0H 3 and 00011 ArMgBr (or ArLi) o= OH 00 OH The compounds of the invention are used to prepare the final 2-lower alkyl-3-lower alkyl-4-aryl-cyclohexenecarboxylic acids and esters according to the following reaction scheme:

C O O R Strong Acid 5 Ar I Ar 000R Ar RI I I RI Typical lactone starting materials for the compounds of the present invention are the lactones of:

'2,3-dibutyl-4-hydroxy-4- (m-trifiuoromethylphenyl) cyclohexanecarboxylic acid,

COOR

3 2-methyl-3-propyl-4-hydroxy-4- (o-methoxy-p-acetoxyphenyl)cyclohexanecarboxylic acid, 2-methyl-3-butyl-4-hydroxy-4- (o,p-diacetoxypheny1) cyclohexanecarboxylic acid,

The following examples illustrate the preparation of the compounds of the invention.

EXAMPLE I 2-methyl-3-ethyl-4-hydroxy-4- (m-anisyl) cyclohexanecarboxylic acid A mixture of 10.0 g. of the lactone of 2-methyl-3-ethyl- 4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid, 10.0 g. of sodium hydroxide, 100 ml. of methanol and 100 ml. of water is stirred and refluxed for two hours and is then diluted with 250 ml. of water and evaporated to remove the methanol. The solution is acidified with dilute hydrochloric acid, and is extracted with ether. The ether solution is rapidly washed with Water, dried over anhydrous magnesium sulfate and filtered. The residue is recrystallized from ether to afford 2-methyl-3-ethyl-4-hydroxy- 4-(m-anisyl)cyclohexanecarboxylic acid; m.p. 203- 204 C.

M,,,,,,,: 2.83, 5.87 and 5.94 (split), 7.78, 8.03, 10.23, 12.80, 14.27 7 (KBr).

NMR (pyr.): 0.63, 0.75, 0.87; 1.46, 1.57; 2.96.

Following the procedure of Example I, but starting with the appropriate lactone, there are prepared:

4 EXAMPLE XV 2-methyl 3 ethyl-4-hydroxy-4-(o-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid; m.p. 164-166 C.

M 2.88, 5.87, 8.13, 10.24, 10.85, 11.52, 13.28 4 (KBr).

NMR (pyr.): 0.67, 0.79, 0.90; 1.47, 1.58; 2.97.

EXAMPLE XVI 2-methyl 3 ethyl-4-hydroxy-4-(o-methoxy-p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, m.p. 118-130 C.

M 2.86, 5.87, 8.31, 9.62, 10.10, 11.04, 11.92 1. (KBr).

NMR (pyr.): 0.65, 0.76, 0.88; 1.46, 1.57; 2.93.

NMR (CDCl 0.67, 0.78, 0.89; 1.02, 1.13; 1.82, 2.57.

EXAMPLE XVII 2-methyl 3 ethyl 4 hydroxy-(o,p-bis-tetrahydro- Example Compound formed C. U.V., max. (KBr) II 2-methyl-3-ethyl-4-hydr0xy-4-(o-anisyl)-cyclo- 187-188 2.82, 5.87 and 5.97 (split), 7.74, 8.10,

hexanccarboxylic acid. 9.67, 13.20 1.

III 2-methyl-3-cthyl-4-hydrcxy-4-(p-thioanisyl)- 189-190 2.83, 5.90, 7.99, 10.37, 11.00, 12.29 7.

cyclohexanecarboxylic acid.

IV 2-methyl-3-ethyl-4-hydroxy-t-(p-tolyl)cyclo- 201-202 2.82, 5.90, 8.10, 10.32, 12.27, 14.10 1.

hexanccarboxylic acid.

V 2-methyl-3-cthyl-4-hydroxy-4-(m-tolyl)cyclo- 154455 2.82, 5.89, 8.01, 8.40, 9.60, 12.78, 13.62 1. hexanccarboxylic acid.

VI 2-methyl-3-ethyl-4-hydroxy-4-(p-trifiuoro- 200-201 2.83, 5.87 and 5.98 (split), 7.50, 8.92, methylphenyl)cyclohexanecarboxylic acid. 9.30, 11.81, 12.02 7.

VII 2-n1ctl1yl-3-ethyl-4-hydroxy-4-(m-trifluoro- 160-170 2.85, 5.83 and 5.97 (split), 7.50, 8.60, methylphenyl)cyclohcxanccarboxylic acid. 8.92, 12.48, 14.22, 14.49

VIII 2-methyl-3-ctl1yl-4-hydroxy-4-(3,4-methylcnc- 196-197 2.82, 5.86 and 5.94 (Split), 8.00, 9.60, dioxyphenyl)cyclohexanecarboxylic acid. 10.63, 12.85 1.

IX 2-metllyl-3-cthyl-4-hydroxy-4-(a-naphthyl)- 177-178 2.82, 5.87 and 5.95 (split), 7.70, 10.13,

cyclohexanecarboxylic acid. 11.60, 12.47, 12.89 1.

X 2-meLhyl-3-ethyl-4-hydr0xy-4-(B-naphthyl)- 216-217 2.85, 5.90, 8.00, 8.58, 11.67, 12.20. 13.83 1.

cyclohexanccarboxylic acid.

XI 2-1netl1yl-3-ethyl-4-hydroxy-4(a-thienyl)- 164-166 2.83, 5.88, 8.02, 9.62, 10.10, 11.79, 14.15,

cyclohexanecarboxylic acid. 14.33 7.

XII 2-methyl-3-ethyl-4-hydroxy-i-benzylcyclohcx- 142-143 2.88, 5.84, 8.23, 10.14, 11.51, 13.03, 14.15 7.

anccarboxylic acid.

XIII 2-methyl-3-propyl-4-(p-anisyl)cyclohcxanc- 196-197 2.84, 5.90, 7.99, 9.57, 11.90, 12.35 7.

carboxylic acid.

EXAMPLE XIV 2-methyl-3-ethyl-4-hydroxy-4- (m-tetrahydropyranyloxyphenyl cyclohexanecarboxylic acid A mixture of 10.0 g. of the lactone of 2-methyl-3-ethyl- 4 hydroxy 4 (m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, 10.0 g. of sodium hydroxide, 100 ml. of methanol and 100 ml. of water is stirred and refiuxed for two hours. It is then diluted with 250 ml. of water and evaporated to remove methanol. The insoluble oily material is removed by extraction with ether and is discarded. 200 ml. of methylene chloride is added to the solution and the mixture is stirred and is maintained at 0-5 C. while making the mixture barely acidic with cold dilute hydrochloric acid. The methylene chloride phase is separated, washed twice with brine, dried over anhydrous magnesium sulfate and evaporated to a residue. The residue is recrystallized from ether to afford Z-methyl- 3-ethyl 4 hydroxy-4-(m-tetrahydropyranyloxyphenyl) cyclohexanecarboxylic acid, m.p. 14915l C.

M 2.83, 5.88, 8.02, 8.98, 9.61, 10.34, 10.92 1 (KBr).

NMR (pyr.): 0.62, 0.73, 0.85; 1.46, 1.58; 2.95.

Following the procedure of Example XIV, there are prepared:

EXAMPLE XVIII 2-rnethyl-3-ethyl-4-hydroxy-4- (m-hydroxyphenyl cyclohexanecarboxylic acid A suspension of 10.0 g. of 2-methyl-3-ethyl-4-hydroxy- 4 (m tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XIV) in 260 ml. of methanol containing 35 ml. of water and 1.5 ml. of 12N hydrochloric acid is stirred at 25 C. for forty minutes. To the resulting clear solution is added 260 ml. of water and 5 ml. of pyridine and the solution is evaporated to remove methanol while precipitating the phenolic hydroxy acid. The mixture is acidified with dilute hydrochloric acid and the product is extracted wifh ether. The ether solution is washed twice with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is recrystallized from ether-methylene chloride to afiford 2-methyl-3-ethyl-4-hydroxy-4-(m-hydroxyphenyl)cyclohexanecarboxylic acid, m.p. 211-213 C.

M 2.96, 3.15, 5.78, 7.50, 9.60, 10.26, 12.68, 13.31, 14.23 2 (KBr).

NMR (pyr.): 0.63, 0.74, 0.85; 1.45, 1.57; 2.92.

EXAMPLE XIX 2-methyl-3 -ethyl-4-hydroxy-4- (o-hydroxyphenyl cyclohexanecarboxylic acid Following the procedure of Example XVIII, but starting with Z-methyl-3-ethyl-4-hydroxy 4 (o-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XV), there is afforded 2-methy1-3-ethyl-4-hydroxy 4 (o-hydroxyphenyl)cyclohexanecarboxylic acid, m.p. 190-191 C.

M 2.82, 3.04, 5.90, 8.06, 10.40, 10.69, 10.92, 13.23; (KBr).

NMR (pyr.): 0.67, 0.78, 0.89; 1.42, 1.53; 2.96.

EXAMPLE XX 2-methyl-3ethy1-4-hydroxy-4- o,p-dihydroxyphenyl) cyclohexanecarboxylic acid EXAMPLE XXI 2-methyl-3 -ethy1-4-hydroxy-4- (o-methoxy-p-hydroxyphenylcyclohexanecarboxylic acid Following the procedure of Example XVIII, but starting with 2-methyl-3-ethyl-4-hydroxy 4 (o-methoxyptetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XVI), there is afforded 2-methyl-3-ethyl-4-hydroxy 4 (o-methoxy-p-hydroxyphenyl) cyclohexanecarboxylic acid, m.p. 128-131 C.

M 2.95, 5.88, 8.31, 9.65, 10.33, 11.97 (KBr).

NMR (pyr.): 0.67, 0.78, 0.90; 1.46, 1.57; 2.94.

EXAMPLE XXII 2-methyl-3-ethyl-4-hydroxy-4-(m-acetoxyphenyl) cyclohexanecarboxylic acid To a solution of 2.0 g. of 2-methyl-3-ethyl-4-hydroxy- 4-(m-hydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XVIII), in 25 ml. of pyridine is added with stirring 3 ml. of acetic anhydride. The solution is maintained at 25 C. for twenty hours and is then hydrolyzed with ice and Water. The oily products are extracted with ether. The ether solution is washed with cold dilute hydrochloric acid to remove pyridine and is then extracted with three cold portions of 7% aqueous potassium carbonate with each successive carbonate wash being immediately acidified with dilute hydrochloric acid. A tacky precipitate from the carbonate solutions is extracted with ether and the combined ether solution is dried and evaporated at 25 C. The residue is recrystallized from ether to afford 2-methyl-3-ethyl-4-hydroxy-4- (m acetoxyphenyl)cyclohexanecarboxylic acid, m.p. 172-173 C.

M 2.83, 5.68, 8.30, 9.63, 10.71, 1273a (KBr).

NMR (pyr.): 0.61, 0.71, 0.82; 1.44, 1.55; 2.94.

EXAMPLE XXIII 2-methyl-3-ethyl-4-hydroxy-4- (oacetoxyphenyl cyclohexanecarboxylic acid Following the procedure of Example XXII, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(o hydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XIX), there is afiorded 2-methyl-3-ethyl-4-hydroxy-4-(oacetoxyphenyl)cyclohexanecarboxylic acid, m.p. 132 133 C.

M 2.82, 5.72, 5.89, 8.20, 8.48, 13.0911. (KBr).

NMR (pyr.): 0.68, 0.80, 0.91; 1.43, 1.55; 2.96.

6 EXAMPLE XXIV 2-methyl-3-ethyl-4-hydroxy-4-(o,p-diacetoxyphenyl) cyclohexanecarboxylic acid Following the procedure of Example XXII, but starting with 2-methy1-3-ethyl-4-hydroxy 4 (o,p-dihydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XX), there is afforded Z-methyl-3-ethyl-4-hydroxy- 4-(o,p-diacetoxyphenyl)cyclohexanecarboxylic acid, m.p. -112 C.

M 2.85, 5.68, 8.10-8.40, 9.80, 10.87; (KBr).

NMR (CD01 0.64, 0.75, 0.86; 0.99, 1.10; 1.89, 2.59.

The o-acetoxyphenyl-hydroxy acids prepared according to Examples XXIII and XXIV are unstable and begin to decompose after a few days at 25 C. They are fully decomposed within two to three weeks at 25 C. The decomposition follows the route:

RQQCOOH CO OH CHZCOE CzHs a Compounds I and II are mixtures of the A and A isomers.

EXAMPLE XXV 2-methyl-3 -ethyl-4-hydroxy-4- (m-chlorophenyl cyclohexanecarboxylic acid 50- hours and then it is cooled in ice and hydrolyzed with 400 ml. of saturated aqueous ammonium acetate. After filtration to remove magnesium, the layers are separated and the organic phase is dried and evaporated to a tacky, semicrystalline residue. Recrystallization from ether or nitromethane affords 9.0 g. of 2-methyl-3-ethyl-4-hydroxy-4- (m-chlorophenyl)cyclohexanecarboxylic acid, m.p. 166- 169 C.

M 2.83, 5.89, 8.01, 12.77, 1379 (KBr).

NMR (pyr.): 0.59, 0.70, 0.80; 1.40, 1.52; 2.92.

The alkyl esters of the compounds of the invention are prepared by treatment of metal salts of the hydroxyacids with an appropriate dialkyl sulfate.

EXAMPLE XXVI Methyl 2-methyl-3-ethyl-4-hydroxy-4-phenylcyclohexanecarboxylate A solution of 4.0 g. of 2-methyl-3-ethyl-4-hydroxy-4- phenylcyclohexanecarboxylic acid and 1.5 g. of sodium hydroxide in 40 ml. of methanol and m1. of dimethylformamide is evaporated under vacuum to a volume of 100 ml. The resulting suspension is stirred and cooled to 15 C. 3.5 ml. of dimethyl sulfate is added and the mixture is stirred at 25 C. for thirty minutes and is then evaporated under vacuum to remove most of the dimethylformamide. The residue of about 1520 ml. of shaken with ether and water, and the ether solution is washed with cold sodium hydroxide, followed by four portions of water. The ether solution is dried and evaporated to a residue. The residue is recrystallized from hexane to afford methyl 2-methyl-3-ethyl-4-hydroxy-4-phenylcyclohexanecarboxylate, m.p. 112113 C.

M 2.87, 5.79, 8.21, 8.55, 13.29, 1430 (KBr).

Calcd. for C H O C, 73.88; H, 8.75. Found: C, 74.00; 8.76.

EXAMPLE XXVII Methyl 2-methyl-3-ethyl-4-hydroxy-4-(p-trifiuoromethylphenyl cyclohexanecarboxylate Following the procedure of Example XXVI, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(p-trifluoromethylphenyl)cyclohexanecarboxylic acid, there is afforded methyl 2-methyl-3-ethyl-4-hydroxy 4 (p trifiuoromethylphenyl)cyclohexanecarboxylate, m.p. 112-113 C.

M,,,,,,,: 2.89, 5.88, 7.49, 7.82, 8.61, 8.90, 9.29, 9.84, 11.81, 12.04;]. (KBr).

Calcd. for C18H2303F3Z C, H, Found: C, 63.07; H, 6.73.

EXAMPLE XXVIII Methyl 2-methyl-3-ethyl-4-hydroxy-4-(rn-trifiuoromethylphenyl) cyclohexanecarboxylate Following the procedure of Example XXVI, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(m-trifiuoromethylphenyl)cyclohexanecarboxylic acid, there is afforded methyl 2-methyl-3-ethyl-4-hydroxy-4-(m trifiuoromethylphenyl)cyclohexanecarboxylate, m.p. 122124 C.

M 2.87, 5.80, 7.50, 8.61, 8.87, 9.24, 12.50, 14.17 (KBr).

Calcd. for C H O F C, 62.79; H, 6.73. Found: C, 62.67; H, 6.73.

Following the procedure of Example XXVI by the selection of the appropriate hydroxy acid and dialkyl sulfate, there are prepared:

ethyl 2-methyl-3-ethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

propyl 2-methyl-3-propyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

ethyl 2-ethyl-3-methyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

ethyl 2,3-dimethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

ethyl 2,3-diethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

butyl Z-methyl-3-ethyl-4-hydroXy-4-benzylcyclohexanecarboxylate,

butyl 2-ethyl-3-butyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

butyl 2-methyl-3-ethyl-4-hydroxy-4-(m-tolyl) cyclohexanecarboxylate, and

butyl 2-methyl-3-propyl-4-hydroxy-4- (m-tolyl cyclohexanecarboxylate.

EXAMPLE XXIX 4-bromoresorcinol bis-tetrahydropyranyl ether To a solution of 100 g. of 4-bromoresorcinol and 70 ml. of dihydropyran in 300 ml. of ether is added 2 ml. of

1.4 N solution of ethereal hydrogen chloride. The temperature of the reaction mixture is maintained at 2532 for 20 hours and then the solution is washed with cold 5% aqueous sodium hydroxide until the washings are colorless. After drying with anhydrous potassium carbonate, the ether solution is evaporated and the viscous oily residue is recrystallized from hexane to atford 112 g. 4-bromoresorcinol bis-tetrahydropyranyl ether, m.p. 60-65. A further-recrystallized, analytical sample melted at 6869.

M 8.48, 8.909.00, 9.62, 10.00, 11.03, (KBr).

Calcd. for C H BrO C, 53.80; H, 5.92. Found: C, 53.94; H, 5.97.

EXAMPLE XXX 3-methoxy-4-bromophenol tetrahydropyranyl ether The combined aqueous alkaline wash from the reaction products of 4-bromoresorcinol with dihydropyran (above) is layered with 300 ml. of ether, stirred and maintained at 05, and acidified with cold dilute hydrochloric acid. The ether solution is washed twice with aqueous potassium bicarbonate, dried, and evaporated to a crystalline residue which is recrystallized from ether-hexane to afford 36 g. of 4-brom0resorcinol l-tetrahydropyranyl ether, m.p. 72-74".

M 2.99, 8.35, 10.11, 10.35, 10.95, 12.47 (KBr).

Calcd. for C H Bi'O C, 48.33; H, 4.79. Found: C, 48.57; H, 4.64.

A solution of 35 g. of 4-bromoresorcinol l-tetrahydropyranyl ether (above) and 8.0 g. of sodium hydroxide in 200 ml. of water and 500 ml. of dimethylformamide is evaporated to a volume of 300 ml. To this is added 13.5 ml. of dimethyl sulfate and the mixture is stirred at 25- 30 for thirty minutes and then diluted with 600 ml. of 3% aqueous sodium hydroxide. Two extractions with ether are made and then the combined ether solution is washed five times with water to remove dimethylformamide. After drying and evaporation, the ether residue is distilled to afford 35 g. of 3-methoxy-4-bromophenol tetrahydropyranyl ether, a colorless oil of b.p. -125 at 0.001 mm.

Calcd. for C H BrO C, 50.18; H, 5.26. Found: C, 49.96; H, 5.17.

The Grignard reagent is prepared under nitrogen from 0.14 mole of the appropriately substituted aryl halide or aralkyl halide and 15 g. of magnesium in 120 ml. of ether and 120 ml. of tetrahydrofuran.

EXAMPLE XXXI Lactone of 2-methyl-3-ethy1-4-hydroxy- 4-phenyl cyclohexanecarboxylic acid 0.12 mole of phenyl magnesium bromide in ether-tetrahydrofuran is stirred vigorously and maintained at 30 C. while a solution of 0.1 mole of ethyl 2-methyl- 3-ethy1-4-ketocyclohexanecarboxylate in 30 ml. of tetrahydrofuran is added over a period of 10 minutes. This mixture is permitted to warm to room temperature. It is then stirred and refluxed for three hours, and is then chilled in an ice and water bath and hydrolyzed by the addition of 200 ml. of saturated aqueous ammonium acetate. The excess magnesium is filtered 01f, washing with 200 ml. of ether, and the filtrate layers are separated. The ether phase is washed with water and 7% aqueous potassium carbonate, and is dried over anhydrous magnesium sulfate. It is evaporated under vacuum leaving an oily res- Following the procedure of Example XXXI there are 1due. The o1ly residue is heated to 120 C. under a presprepared:

Example Compound formed lactone of- Ar in .ArMgBr M.P., 0. Infrared spectra A). m

I 2-metl1y1-3-ethy114-hydroxy-4-(m-anisyl)- m-Anisyl 104-105 5.71, 8.13, 9.14, 9.73, 9.81, 11.18,

cyclohexanecarboxylic acid. 12.74 1.1. (KBr) XXXII Z-methyl-3-ethylP4-hydroxy-4-(o-anisyD- o-Anisyl Impure oil 5.70, 8.04, 9.71, 9.89, 13.21 p.

cyclohexanecarboxylic acid.

XXXIV 2-methyl-3-ethyl-4-hydroxy-4-(pdiethylaminop-Diethylaminoethoxypheuyl- B.P. at 0.001 5.70, 8.00, 8.45, 9.14, 9.86,

ethoxyphenyl)cyclohexanecarboxylic acid. mm. 180-190 12.00 p.

XXXV 2-methyl-3-ethyl 4-hydr0xy-4-(p-thioauisyl)- p-Thioanisyl 91- 5.71, 9.13, 9.83, 11.97, 12.70 p.

cyclohexanecarboxylic acid. (KB r) XXXVI 2-methyl-3-ethyl-4-hydroxy-4-(p-tolyD- p-Tolyl 96-97 5.73, 8.36, 9.12, 9.86, 12.26 p. cyclohexanecar'boxyhc acid. (KBr) XXXVII 2-methy1-3-ethyl;4-hydroxy-4-(m-tolyl)- m-Tolyl 117-118 5.72, 8.01, 9.16, 9.83, 12.55,

cyclohexanecarboxylic acid. 12.73 Br) XXXVIIL..- Z-methyl-3-ethyl54-hydroxy-4-(m-tetrahydrom-Tetrahydropyranyloxy- 98-112 5.70, 8.48, 9.86, 10.31, 12.64,

pyranyloxyphenyl)cyclohexanecarboxylic acid. phenyl. 12.72 1. Br)

XXXIX 2-methy1-3-ethyl-4-hydroxy-4-(o-tetrahydroo-Tetrahydropyranyloxy- 93-98 5.70, 8.10, 9 89, 10.37, 10.87,

pyranyloxyphenyl)cyclohexanecarboxylic acid. phen 11.47, .29 ,1. (KB I) XL 2-methyl-3-ethyl54-hydroxy-i-(o-methdxy-po-Methoxy-p-tetrahydro- Impnre oil 5.70, 7.83, 8.32, 9.60, 9.87, 10.16,

tetrahydropyranyloxyphenyl)cycloltexanepyranyloxyphenyl. 11.01 p. carboxylic acid.

XLI 2-methy1-3-etliyl;4-hydroxy-4-(o,p-bis-tctrao,p-Bistetrahydrodo 5.69, 7.90, 8.50, 9.60, 11.07, p hydropyranyloxyphenyl)cyclohexane pyranyloxyphenyl. 11.42 p. carboxylic acid.

XLII 2-methyl-3ethyl-4-hydr0xy-4-(3,4-methy1ene- 3,4-methylenedioxyphenyL... 132-133.... 5 72, 8.10, 9.12, 9.65, 9.82,

dioxyphenyl)cyclohexanecarboxylic acid. 10.77, 12.25 g. (KBr) XLIII 2-methyl-3-ethyl-4-hydroxy-4-(a-uaphthyD- a-Naphthyl Impure 011 5 71, 8.25, 8 94, 9.60, 9.90,

cyclohexanecarboxylic acid. 1 .42, 12.82 is sure of 0.001 mm. to remove volatiles. The residue is then chromatographed on a column of neutral alumina, 25 and elution with benzene and ether affords a series of lactonic fractions. Those possessing similar infrared spectra are combined and recrystallized from hexane to atford the lactone of 2-methy1-3-ethyl-4-hydroxy-4-phenyl- What is claimed is:

1. 2-methyl-3-ethyl-4-hydroxy-4-(m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid.

2. 2-methyl-3-ethyl-4-hydroxy-4-(o tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid.

3. 2-methyl-3-ethyl 4 hydroxy-4-(o-methoxy-p-tetracyclohexanecarboxylic acid, mp. 82-83" C. having the in- 30 hydroiayranyloxyphenyl) cyclohexanecarboxylic acid.

4. 2-methy1-3-ethyl 4 hydroxy4-(o,p-bis-tetrahydr0- frared spectrum:

M 5.71, 8.05, 9.11, 9.84, 10.79, 13.05 1. (KBr).

Calcd. for C H O C, 78.65; H, 8.25. Found: C,

The steric structure is confirmed with NMR as follows: 35

pyranyloxyphenyl)cyclohexanecarboxylic acid.

No references cited.

NORMA S. MILESTONE, Primary Examiner ORM PO-IOSO (1069) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 7 b September ZLL, 197A Karmas, George Page 1 Inven-tor(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Column 1, line 4- in title, the word Cyclohexanecarboxy11c should read Cyclohexenecarboxylic In Column 1, line 63, the words "of aryl" should read 'of an aryl In Colurm 2, line 5 the words "Serial NO. 622, 311" should read Serial No. 662, 311

In Column l, line 67, the word wifh" should read with InColumn 6, line 57. his number "1379" should read 13.79

In Column 7 line 10, the numbers 97 4.00; 8.7g" should read L00 1-1, 8.76 V

In Column 8, line 1, the number "ll-I should read USCOMM-DC scan-P09 U3 GOVERNMENT PRINT NG OFFICE: 869 9 30 F ORM PO-1 O50 (10-69) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,838,172

Dated September 24, 1974 Inventor(s) Karmas, George Page 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 9, (in table) the first two examples, in column 1 should appear as shown below:

2- -n:c thyle 3- -ethy1= l.-hydroxyl- (o-anisyl) 9 i. i cyc lohexanccarboxylic. acid In Column 10, (in table) Example XLI under "infrared spectra max" "11.07, 1" should read 11.07,

Signed and Scaled this eighteenth 4 D ay 0f November 19 75 [SEAL] A nest.-

RUTH C. MASON Alluring Office C. MARSHALL DANN 'mnmissimu'r 111' Pu runs and Tradcmurkx USCOMM-DC 60316-P69 u s GOViRNMENT murmur. ornc: a 93 o 

